Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT, but evidence for their effectiveness and safety in larger animals is lacking. HD transgenic sheep express the full-length human HTT with 73 CAG repeats. AAV9 was used to deliver unilaterally to HD sheep striatum an artificial miRNA targeting exon 48 of the human HTT mRNA under control of two alternative promoters: U6 or CβA. The treatment reduced human mutant (m) HTT mRNA and protein 50-80% in the striatum at 1 and 6 months post injection. Silencing was detectable in both the caudate and putamen. Levels of endogenous sheep HTT protein were not affected. There was no significant loss of neurons labeled by DARPP32 or NeuN at 6 months after treatment, and Iba1-positive microglia were detected at control levels. It is concluded that safe and effective silencing of human mHTT protein can be achieved and sustained in a large-animal brain by direct delivery of an AAV carrying an artificial miRNA

Study protocol: population screening for colorectal cancer by colonoscopy or CT colonography: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is the second most prevalent type of cancer in Europe. Early detection and removal of CRC or its precursor lesions by population screening can reduce mortality. Colonoscopy and computed tomography colonography (CT colonography) are highly accurate exams and screening options that examine the entire colon. The success of screening depends on the participation rate. We designed a randomized trial to compare the uptake, yield and costs of direct colonoscopy population screening, using either a telephone consultation or a consultation at the outpatient clinic, versus CT colonography first, with colonoscopy in CT colonography positives.</p> <p>Methods and design</p> <p>7,500 persons between 50 and 75 years will be randomly selected from the electronic database of the municipal administration registration and will receive an invitation to participate in either CT colonography (2,500 persons) or colonoscopy (5,000 persons) screening. Those invited for colonoscopy screening will be randomized to a prior consultation either by telephone or a visit at the outpatient clinic. All CT colonography invitees will have a prior consultation by telephone. Invitees are instructed to consult their general practitioner and not to participate in screening if they have symptoms suggestive for CRC. After providing informed consent, participants will be scheduled for the screening procedure. The primary outcome measure of this study is the participation rate. Secondary outcomes are the diagnostic yield, the expected and perceived burden of the screening test, level of informed choice and cost-effectiveness of both screening methods.</p> <p>Discussion</p> <p>This study will provide further evidence to enable decision making in population screening for colorectal cancer.</p> <p>Trial registration</p> <p>Dutch trial register: NTR1829</p

Swallowing Assessment in Parkinson's Disease:Patient and Investigator Reported Outcome Measures are not Aligned

This study determines the relationship between patient and investigator reported outcome measures (PROMs versus IROMs) on oropharyngeal dysphagia (OD) in Parkinson's disease (PD). The PROMs used are the MD Anderson Dysphagia Inventory (MDADI) and the Dysphagia Severity Scale (DSS). The IROMs used are fiberoptic endoscopic evaluation of swallowing (FEES) and videofluoroscopy of swallowing (VFS). Ninety dysphagic PD patients were included. Multilayer perceptron (MLP) neural network analysis was used to investigate the relationship between PROMs and IROMs on OD in PD. MLP neural network analysis showed a moderate agreement between PROMs and IROMs, with an area under the curve between 0.6 and 0.7. Two-step cluster analysis revealed several clusters of patients with similar scores on FEES and/or VFS variables, but with significant different scores on MDADI and DSS variables. This study highlights that there are PD patients with similar FEES and/or VFS findings that cannot be lumped together under the same pathophysiological umbrella due to their differences in PROMs. Since the exact origin of these differences is not fully understood, it seems appropriate for the time being to take into account the different dimensions of OD during the swallowing assessment so that they can be included in a patient-tailored treatment plan

Segmentation and size measurement of polyps in ct colonography,” Lecture Notes Comput

Abstract. Virtual colonoscopy is a relatively new method for the detection of colonic polyps. Their size, which is measured from reformatted CT images, mainly determines diagnosis. We present an automatic method for measuring the polyp size. The method is based on a robust segmentation method that grows a surface patch over the entire polyp surface starting from a seed. Projection of the patch points along the polyp axis yields a 2D point set to which we fit an ellipse. The long axis of the ellipse denotes the size of the polyp. We evaluate our method by comparing the automated size measurement with those of two radiologists using scans of a colon phantom. We give data for inter-observer and intra-observer variability of radiologists andour method as well as the accuracy and precision.

Prevalence of adjustment disorder among cancer patients, and the reach, effectiveness, cost-utility and budget impact of tailored psychological treatment:Study protocol of a randomized controlled trial

Contains fulltext : 215506.pdf (publisher's version ) (Open Access)BACKGROUND: Information on the prevalence of adjustment disorders among cancer patients and the value of psychological interventions in this group of patients is limited. This study investigates the prevalence of adjustment disorders among cancer patients as well as the reach, effectiveness, cost-utility and budget impact of a tailored psychological intervention. METHOD: This study consists of two parts. Part 1 is an observational study among a representative group of mixed cancer patients after cancer treatment on the prevalence of adjustment disorder as well as the uptake (i.e. reach) of psychological treatment. In Part 2, patients diagnosed with an adjustment disorder are invited to participate in a randomized controlled trial. Patients will be randomized to the intervention (access to the tailored psychological intervention) or control group (waitlist period of 6 months). The psychological intervention consists of three modules: one module containing psycho-education (3 sessions, all patients) and two additional modules (maximum of 6 sessions per module) provided as continuum, in case needed. Module 2 and 3 can consist of several evidence-based interventions (e.g. group interventions, mindfulness, eHealth) The primary outcome is psychological distress (HADS). Secondary outcomes are mental adjustment to cancer (MAC) and health-related quality of life (EORTC QLQ-C30). To assess the cost-utility and budget impact, quality of life (EQ-5D-5 L) and costs (iMCQ and iPCQ) will be measured. Measures will be completed at baseline and 3 and 6-months after randomization. DISCUSSION: This study will provide data of the prevalence of adjustment disorders and the reach, effectiveness, cost-utility and budget impact of a tailored psychological intervention. TRIAL REGISTRATION: Netherlands Trial Register identifier: NL7763. Registered on 3 June 2019

Polyp measurement and size categorisation by CT colonography: effect of observer experience in a multi-centre setting.

The extent measurement error on CT colonography influences polyp categorisation according to established management guidelines is studied using twenty-eight observers of varying experience to classify polyps seen at CT colonography as either 'medium' (maximal diameter 6-9 mm) or 'large' (maximal diameter 10 mm or larger). Comparison was then made with the reference diameter obtained in each patient via colonoscopy. The Bland-Altman method was used to assess agreement between observer measurements and colonoscopy, and differences in measurement and categorisation was assessed using Kruskal-Wallis and Chi-squared test statistics respectively. Observer measurements on average underestimated the diameter of polyps when compared to the reference value, by approximately 2-3 mm, irrespective of observer experience. Ninety-five percent limits of agreement were relatively wide for all observer groups, and had sufficient span to encompass different size categories for polyps. There were 167 polyp observations and 135 (81%) were correctly categorised. Of the 32 observations that were miscategorised, 5 (16%) were overestimations and 27 (84%) were underestimations (i.e. large polyps misclassified as medium). Caution should be exercised for polyps whose colonographic diameter is below but close to the 1-cm boundary threshold in order to avoid potential miscategorisation of advanced adenomas

Polyp measurement and size categorisation by CT colonography: effect of observer experience in a multi-centre setting

The extent measurement error on CT colonography influences polyp categorisation according to established management guidelines is studied using twenty-eight observers of varying experience to classify polyps seen at CT colonography as either 'medium' maximal diameter 6-9 mm) or 'large' (maximal diameter 10 mm or larger). Comparison was then made with the reference diameter obtained in each patient via colonoscopy. The Bland-Altman method was used to assess agreement between observer measurements and colonoscopy, and differences in measurement and categorisation was assessed using Kruskal-Wallis and Chi-squared test statistics respectively. Observer measurements on average underestimated the diameter of polyps when compared to the reference value, by approximately 2- 3 mm, irrespective of observer experience. Ninety-five percent limits of agreement were relatively wide for all observer groups, and had sufficient span to encompass different size categories for polyps. There were 167 polyp observations and 135 (81%) were correctly categorised. Of the 32 observations that were miscategorised, 5 (16%) were overestimations and 27 (84%) were underestimations (i.e. large polyps misclassified as medium). Caution should be exercised for polyps whose colonographic diameter is below but close to the 1-cm boundary threshold in order to avoid potential miscategorisation of advanced adenomas